Corroles
Corroles are tetrapyrrole macrocycles that are closely related to porphyrins, with one carbon atom less in the outer periphery and one NH proton more in their inner core. The corroles are much less known than porphyrins and their synthesis was considered to be very complex. A simple procedure for corrole synthesis and their use as chemical catalysts have been disclosed in Gross et al. U.S. Pat. No. 6,541,628, assigned to the same applicant.
U.S. Pat. No. 6,730,666, in which the applicant is a co-assignee, discloses porphyrins and corroles useful for inhibition of cell proliferation mediated by growth factor receptor tyrosine kinase activity, for example, for inhibition of angiogenesis, or vascular smooth muscle cell proliferation in disorders including atherosclerosis, hypertrophic heart failure and postsurgical restenosis, and inhibition of cell proliferation and migration in the treatment of primary tumors and metastasis. The sole corrole disclosed in this patent was shown to inhibit the appearance of lung metastasis in an animal model.
New selectively-substituted corroles are disclosed in Gross et al. U.S. Pat. No. 6,939,963 assigned to the same applicant as well as their use for tumor detection and treatment, in photovoltaic devices, as catalysts and as intermediates.
The inventors have demonstrated in two recent publications that the iron and manganese complexes of 5,10,15-tris(pentafluorophenyl)-2,17-bis(sulfonic acid)-corrole disclosed in U.S. Pat. No. 6,939,963 are excellent catalysts for decomposition of two important reactive molecules, hydrogen peroxide (H2O2) and peroxynitrite (HOONO) (Mahammed et al., 2005; Mahammed and Gross., 2002). Firm evidence in favor of a disproportionation mechanism was provided for both H2O2 and HOONO: they first serve as oxidants for transferring the Mn(III) corrole into the (oxo)Mn(V) complex, which then utilizes the same molecules as reductants for returning to Mn(III). Less detailed mechanistic insight was obtained for the iron complex, but its catalytic rates were found to be faster than those of the Mn complex and it apparently induced isomerization rather than disproportionation of peroxynitrite. The fast action of the Fe complex and the unique mechanism adopted by the Mn complex suggest a significant added value of these complexes in the continuous efforts devoted to the development of synthetic catalysts that may either neutralize or avoid the formation of reactive oxygen and nitrogen species.
Besides being potent catalysts for decomposition of peroxynitrite in purely chemical systems, the above metallocorroles (of unique amphiphilicity and bipolarity due to the positioning of sulfonic acid head groups on the otherwise lipophilic corrole) were also shown to have large affinity to various proteins (Haber et al., 2008; Mahammed et al., 2004), a very important factor that may be used for selective delivery purposes.
Another publication by the inventors (Gershman et al., 2007) discloses DNA binding and catalytic properties of novel positively charged Mn complex of corrole containing pyridinium groups.
Cardiovascular Diseases and Disorders
Cardiovascular diseases and disorders involve the heart and/or blood vessels and include, for example, congestive heart failure (CHF) or heart failure, a condition in which the heart cannot pump enough blood to the body's other organs and may result from (i) narrowed arteries that supply blood to the heart muscle—coronary artery disease; (ii) past heart attack, or myocardial infarction, with scar tissue that interferes with the heart muscle's normal work; (iii) high blood pressure; (iv) heart valve disease due to past rheumatic fever or other causes; (v) primary disease of the heart muscle itself, called cardiomyopathy; (vi) congenital heart defects; (vii) infection of the heart valves and/or heart muscle itself, i.e., endocarditis and/or myocarditis.
Other cardiovascular diseases or disorders include myocardial infarction, the rapid development of myocardial necrosis that usually results from plaque rupture with thrombus formation in a coronary vessel, resulting in an acute reduction of blood supply to a portion of the myocardium; myocardial ischemia, a condition in which oxygen deprivation to the heart muscle is accompanied by inadequate removal of metabolites because of reduced blood flow or perfusion; and atherosclerosis.
Atherosclerosis is the leading cause of death in the developed world and is predicted to be the leading cause of death in the developing world. It is a chronic vascular disease characterized by cholesterol accumulation in the arterial wall, including macrophage foam cell formation, secondary to blood lipoproteins uptake. This disease may develop into a complete blockage of the arteries, resulting in a heart attack or a stroke. A major risk factor for the disease is high levels of blood cholesterol and the oxidation of low-density lipoproteins (LDL) (Aviram, 1995; Steinberg et al., 1989). Oxidized LDL is taken up by macrophages in the arterial wall in a non-controlled fashion, thus leading to the formation of cholesterol-loaded foam cells (Dhaliwal and Steinbrecher, 1999; Aviram, 1996), the hallmark of early atherosclerosis.
It has been shown that both the risk and the rate of development of atherosclerosis are increased in diabetics. A molecular mechanism providing a link between the two disorders was described by Griffin et al. (2001) who showed that glucose regulates expression of the macrophage scavenger receptor CD36 at the level of translation. The increased translation of macrophage CD36 transcript under high glucose conditions provides a mechanism for accelerated atherosclerosis in subjects with diabetes.
Oxidative Stress and Atherosclerosis
The imbalance between the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and the ability of biological systems to readily detoxify the reactive intermediates (or easily repair the resulting damage) is commonly called oxidative stress. Accumulating strong evidence points towards the involvement of oxidative stress in neurodegenerative diseases (Alzheimer's, Parkinson's, and the like) and in the biological aspects of ageing, as well as in atherosclerosis development (Barber et al., 2006; Beal, 2002; Moreira et al., 2005; Stocker and Keaney, 2005).
Hydrogen peroxide (H2O2) and peroxynitrite (HOONO) are two representatives of ROS, with the latter also being an RNS. In addition to the intrinsic reactivity of hydrogen peroxide and peroxynitrite toward certain organic molecules, both of them are precursors for .OH radical and the latter, to .NO2 radical as well. These radical species (and secondary radicals derived from them) are considered to be the main species that damage a very large variety of molecules, including those that are of vital importance for the health of the living systems (Halliwell and Gutteridge, 1999).
Antioxidants are substances that may protect lipoproteins, other biomolecules and cells from the damage caused by free radicals. Natural antioxidants include, for example, glutathione, vitamin C, vitamin E and punicalagin as well as enzymes such as catalase, superoxide dismutase, paraoxonases and various peroxidases. Paraoxonases are a group of enzymes involved in the hydrolysis of organophosphates. Paraoxonases 1 and 3 (PON1 and PON3) function as antioxidants, by preventing the oxidation of LDL, while paraoxonase 2 (PON2) can protect cells against oxidative damage. Punicalagins are large polyphenol tannins, which were found to be the major component responsible for pomegranate juice's antioxidant and health benefits.
The problem unique to peroxynitrite is that, in contrast to all other ROS and RNS and their precursors, there is no known biological defense system against it and most natural antioxidants are very poor scavengers of peroxynitrite (Bartletta et al., 1995; Szabó et al., 2007). This call for the development of synthetic molecules that could act on and neutralize peroxynitrite by one or more of the following ways: a) interfere with its formation by eliminating its precursors (superoxide anion and nitric oxide); b) decompose it to biologically benign products; c) repair the damage caused by it.
As mentioned above, we have shown that the iron and manganese complexes of 5,10,15-tris(pentafluorophenyl)-2,17-bis(sulfonic acid)-corrole are excellent catalysts for decomposition of hydrogen peroxide and peroxynitrite (Mahammed et al., 2005; Mahammed and Gross., 2002).